Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

[Brain Stem and Para-Brain Stem Lesions].

Surgeries for brainstem lesions and adjacent areas needs meticulous manipulation in the profoundly deep surgical field. Moreover, it is associated with a high risk of complications pertinent to resection. The opportunity for a surgeon to amass extensive surgical experience in these lesions is limited. Additionally, the reduced tissue mobility in the brainstem, compared to other lesions, makes selecting the optimal surgical approach critical. Preoperative simulation is pivotal in surmounting these challenges. However, the limitations of preoperative simulations should be recognized in accurately depicting diminutive vessels and cranial nerves around the brainstem. Incorporating intraoperative anatomical observations and data from intraoperative monitoring into a surgical strategy is imperative. Here, we present three cases in which we believe preoperative simulation was effective; a cavernous hemangioma of the brainstem, trochlear schwannoma, and diffuse midline glioma in the pons.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Deep-Learning Uncovers certain CCM Isoforms as Transcription Factors.

BACKGROUND: Cerebral Cavernous Malformations (CCMs) are brain vascular abnormalities associated with an increased risk of hemorrhagic strokes. Familial CCMs result from autosomal dominant inheritance involving three genes: KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). CCM1 and CCM3 form the CCM Signal Complex (CSC) by binding to CCM2. Both CCM1 and CCM2 exhibit cellular heterogeneity through multiple alternative spliced isoforms, where exons from the same gene combine in diverse ways, leading to varied mRNA transcripts. Additionally, both demonstrate nucleocytoplasmic shuttling between the nucleus and cytoplasm, suggesting their potential role in gene expression regulation as transcription factors (TFs). Due to the accumulated data indicating the cellular localization of CSC proteins in the nucleus and their interaction with progesterone receptors, which serve dual roles as both cellular signaling components and TFs, a question has arisen regarding whether CCMs could also function in both capacities like progesterone receptors. METHODS: To investigate this potential, we employed our proprietary deep-learning (DL)-based algorithm, specifically utilizing a biased-Support Vector Machine (SVM) model, to explore the plausible cellular function of any of the CSC proteins, particularly focusing on CCM gene isoforms with nucleocytoplasmic shuttling, acting as TFs in gene expression regulation. RESULTS: Through a comparative DL-based predictive analysis, we have effectively discerned a collective of 11 isoforms across all CCM proteins (CCM1-3). Additionally, we have substantiated the TF functionality of 8 isoforms derived from CCM1 and CCM2 proteins, marking the inaugural identification of CCM isoforms in the role of TFs. CONCLUSIONS: This groundbreaking discovery directly challenges the prevailing paradigm, which predominantly emphasizes the involvement of CSC solely in endothelial cellular functions amid various potential cellular signal cascades during angiogenesis.

Microsurgical Resection of Giant Radio-Induced Cavernous Malformation: 2- Dimensional Video.

Radioinduced cavernous malformations (RICMs) are low-flow, angiographically occult vascular lesions. Giant radioinduced cavernous malformations (GRICMs) are a subtype of RICMs that are characterized by their large size. GRICMs are defined as RICMs that are larger than 3 cm in diameter.1 They are uncommon conditions accounting for 0.1% to 0.5% among patients who have received radiation therapy for head and neck cancer or brain tumors.2,3 The risk of developing GRICMs increases with the dose of radiation received and the length of time since radiation exposure.4 Other factors that may increase the risk of developing GRICMs include age, genetic predisposition, and underlying medical conditions.5 Due to the relatively low incidence of GRICMs and the limited number of studies on this condition, there are limited data about the management of this condition. This case report describes a 12-year-old female who was previously treated for a pilocytic astrocytoma in 2012. After undergoing stereotactic biopsy and whole-brain radiotherapy (50 gray in 28 sections), she was diagnosed with a radioinduced cavernous malformation in 2016 during follow-up imaging. The RICM was managed conservatively with imaging follow-up, which showed no increase in size between 2016 and 2019. However, in 2020, the patient experienced a seizure episode associated with left-sided hemiplegia. Further investigation with cranial magnetic resonance imaging and digital subtraction angiography showed a mixed-intensity image and surrounded by a low signal intensity rim on T2-weighted images, representing hemosiderin in the right central lobe, with intense perilesional edema, with no enhancement. Given the size and location of the mass, the patient underwent microsurgical resection of the RICM (Video 1). The surgery was successful, and the lesion was successfully resected. This case highlights the importance of careful monitoring for RICMs in patients who have received radiation therapy, as well as the potential for these lesions to cause significant symptoms and disability. The case also demonstrates that surgical intervention may be necessary in some cases to manage RICMs and that microsurgical resection can be an effective treatment option. The patient gave informed consent for surgery and video recording.

Keyhole Retrosigmoid Craniotomy for Lateral Pontine Cavernous Malformation.

With improvements in anesthesia, monitoring, and peroperative care, the surgical removal of intrinsic brainstem pathology has become a possibility.1 Although surgical removal of deep-seated lesions continues to have significant morbidity, at least temporarily, associated with it, removal of exophytic lesions can be accomplished with little disability for the patient. The key to a good outcome, when removing cerebral cavernous malformation, is preservation of adjacent neurovascular bundles, use of sharp dissection over blunt pulling, judicious use of cautery in and around the brainstem, and preservation of the developmental venous anomaly, when present. The authors present a case of a lateral pontine cerebral cavernous malformation that was exophytic at the lateral and peritrigeminal safe entry zones.2 Neuromonitoring was used an adjunct to ensure safety of the procedure. The lesion is accessed using a keyhole retrosigmoid craniotomy (Video 1). We do not routinely use lumbar drains for these procedures as careful arachnoid dissection can result in adequate cerebrospinal fluid release. The window of access to this area is between CN 5 and the CN 7/8 complex. The arachnoid over the nerves is preserved, but the layer between the nerves is exposed to gain access to the lateral pons. The lesion is sharply dissected from the lateral pons, taking care to save the developmental venous anomaly, from which this lesion arises.

Cerebral cavernous malformation proteins, CCM1, CCM2 and CCM3, are decreased in metastatic lesions in a murine breast carcinoma model.

Three genes are associated with cerebral cavernous malformations (CCMs): CCM1, CCM2 and CCM3. These genes participate in microvascular angiogenesis, cell-to-cell junctions, migration and apoptosis. We evaluated the expression in vivo of CCM genes in primary tumors and metastastases in a murine model of metastatic breast carcinoma. We used cell lines obtained from metastasis of 4T1, 4TLM and 4THM breast cancer to liver and heart. These cells were injected into the mammary ridge of Balb/C female mice. After 27 days, the primary tumors, liver and lung were removed and CCM proteins were assessed using immunohistochemistry and western blot analysis. CCM proteins were expressed in primary tumor tissues of all tumor-injected animals; however, no CCM protein was expressed in metastatic tumor cells that migrated into other tissues. CCM proteins still were observed in the lung and liver tissue cells. Our findings suggest that CCM proteins are present during primary tumor formation, but when these cells develop metastatic potential, they lose CCM protein expression. CCM protein expression was lost or reduced in metastatic tissues compared to the primary tumor, which indicates that CCM proteins might participate in tumorigenesis and metastasis.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.

Pediatric cerebral cavernous malformations and stereotactic radiosurgery: an analysis of 50 cases from a multicentric study.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are the second most common vascular anomaly affecting the CNS in children. Although stereotactic radiosurgery (SRS) has been proposed as an alternative to microsurgery in the management of selected cases in adults, there is a paucity of studies focusing on pediatric patients. The aim of this study was to present the outcomes and associated risks of SRS in this subgroup of patients. METHODS: This retrospective multicenter study included pediatric patients treated with single-session SRS for CCMs. The annual hemorrhage rate (AHR) was calculated before and after SRS in hemorrhagic lesions. The Engel classification was used to describe post-SRS epileptic control. Adverse radiation effects (AREs) and the occurrence of new neurological deficits were recorded. RESULTS: The study included 50 patients (median age 15.1 [IQR 5.6] years) harboring 62 CCMs. Forty-two (84%) and 22 (44%) patients had a history of hemorrhage or epilepsy prior to SRS, respectively. The AHR from diagnosis to SRS excluding the first hemorrhage was 7.19 per 100 CCM-years, dropping to 3.15 per 100 CCM-years after treatment. The cumulative risk of first hemorrhage after SRS was 7.4% (95% CI 0%-14.3%) at 5 years and 23.6% (95% CI 0%-42.2%) at 10 years. Eight hemorrhagic events involving 6 CCMs in 6 patients were recorded in the post-SRS follow-up period; 4 patients presented with transient symptoms and 4 with permanent symptoms. Of the 22 patients with pre-SRS seizures, 11 were seizure free at the last follow-up (Engel class I), 6 experienced improvement (Engel class II or III), 5 had no improvement (Engel class IVA or IVB), and 1 experienced worsening (Engel class IVC). Radiographic AREs were documented in 14.5% (9/62) of CCMs, with 4 being symptomatic. CONCLUSIONS: Single-session SRS reduces the CCM hemorrhage rate in the pediatric population and provides adequate seizure control.

Towards a neurocognitive profile in familial cerebral cavernous malformations.

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

Quantitative image signature and machine learning-based prediction of outcomes in cerebral cavernous malformations.

PURPOSE: There is increasing interest in novel prognostic tools and predictive biomarkers to help identify, with more certainty, cerebral cavernous malformations (CCM) susceptible of bleeding if left untreated. We developed explainable quantitative-based machine learning models from magnetic resonance imaging (MRI) in a large CCM cohort to demonstrate the value of artificial intelligence and radiomics in complementing natural history studies for hemorrhage and functional outcome prediction. MATERIALS AND METHODS: One-hundred-eighty-one patients from a prospectively registered cohort of 366 adults with CCM were included. Fluid attenuated inversion recovery (FLAIR) T2-weighted brain images were preprocessed, and CCM and surrounding edema were segmented before radiomic feature computation. Minority class oversampling, dimensionality reduction and feature selection methods were applied. With prospective hemorrhage as primary outcome, machine learning models were built, cross-validated, and compared using clinico-radiologic, radiomic, and combined features. SHapley Additive exPlanations (SHAP) was used for interpretation to determine the radiomic features with most contribution to hemorrhage prediction. RESULTS: The highest performances in hemorrhage predictions on the test set were combining radiomic and clinico-radiological features with an area under the curve (AUC) of 83% using linear regression and selected features, and an F1 score of 61% and 85% sensitivity using K-nearest neighbors with principal component analysis (PCA). Multilayer perceptron had the best performance predicting modified Rankin Scale ≥ 2 with an AUC of 74% using PCA derived features. For interpretation of the selected radiomic signature XGBoost model, Shapley additive explanations highlighted 6 radiomic features contributing the most to hemorrhage prediction. CONCLUSION: Quantitative image-based modeling using machine learning has the potential to highlight novel imaging biomarkers that predict hemorrhagic and functional outcomes, ensuring more precise and personalized care for CCM patients.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Cavernous venous malformations in and around the central nervous system. Part 1: Dural and extradural.

Cavernous-type malformations are venous lesions that occur in multiple locations throughout the body, and when present in the CNS, they have canonically been referred to as cavernomas, cavernous angiomas, and cerebral cavernous malformations. Herein all these lesions are referred to as "cavernous venous malformations" (CavVMs), which is congruent with the current International Society for the Study of Vascular Anomalies classification system. Even though histologically similar, depending on their location relative to the dura mater, these malformations can have different features. In Part 1 of this review, the authors discuss and review pertinent clinical knowledge with regard to CavVMs as influenced by anatomical location, starting with the dural and extradural malformations. They particularly emphasize dural CavVMs (including those in the cavernous sinus), orbital CavVMs, and spinal CavVMs. The genetic and histopathological features of CavVMs in these locations are reviewed, and commonalities in their presumed mechanisms of pathogenesis support the authors' conceptualization of a spectrum of a single disease entity. Illustrative cases for each subtype are presented, and the pathophysiological and genetic features linking dural and extradural to intradural CavVMs are examined. A new classification is proposed to segregate CavVMs based on the location from which they arise, which guides their natural history and treatment.

Return to Play in Collision Sport After Hemorrhages of a Cerebral Cavernoma.

ABSTRACT: Discovering a cerebral vascular malformation in an athlete should lead to evaluating hemorrhagic risk, notably in contact sports. Cavernous angioma is one of the most frequent pathologies in this context. It can be identified by a hemorrhage, the onset of an epileptic seizure, or, increasingly so, incidentally, while performing a medical examination for another reason. Whether sports practice is a risk factor for hemorrhage is unclear in available literature. When treatment is needed, surgery remains the gold standard. Currently, little data are available on the possibility of resuming contact sports after craniotomy. We report the case of a rugby player who underwent surgery for intracerebral cavernoma. We provide details on how the player was finally cleared to resume rugby practice and on the therapeutic management of this lesion.

Cerebral Cavernous Malformations Patient Perception Analysis via Social Media.

BACKGROUND: The rise of social media has allowed for individuals and patients to connect with each other and influence patient behavior. This study aimed to improve our understanding of the patients' experience with cerebral cavernous malformations (CCM) via social media. METHODS: Instagram and Twitter were searched using terms of ("cavernoma," "cavernous malformations," "cavernous angioma," or "cav mal"). Public Instagram posts tagged with "#cavernoma" and "@cavernoma" identified 327 posts that directly included a patient's own experience. Twitter posts that included "#cavernoma" and "@cavernoma" were searched, yielding 75 after eliminating those that did not pertain to the patient's own experience. The posts and tweets were coded for relevant themes related to their experience with the disease. RESULTS: Overall, more patients are using Instagram (n = 327) over Twitter (n = 84) to share their personal experience with CCM with a trend for male patients to use Twitter more compared to females with a female predominance in Instagram. A total of 277 of 327 (84.7%) Instagram posts and 67 of 84 (89.3%) Twitter posts were made after the patient's surgery. The most common theme on Instagram was focused on the postoperative rehabilitation process and mobility support (52.0 and 24.5%, respectively). Other common themes present on Twitter and Instagram were recounting symptoms and complications and life satisfaction (26.0 and 24.2%, respectively). Cavernoma patients prior to surgery were more likely to discuss on Instagram their symptoms (p = 0.001), fear of bleeding (p < 0.001), and mental health (p = 0.014). Postoperatively, cavernoma patients were more likely to discuss disability than they were preoperatively (p = 0.001). CONCLUSION: Social media platforms offer a communication tool for patients with CCM patients to share their experience with other patients and the general public and portrays their personal experience with CCM. These platforms allow for physicians to better understand the patient experience following cavernoma surgery.

Comprehensive CCM3 Mutational Analysis in Two Patients with Syndromic Cerebral Cavernous Malformation.

Cerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genes KRIT1(CCM1), MGC4607(CCM2), and PDCD10(CCM3). Patients affected by the PDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form of KRIT1 or CCM2 mutations and six patients with a sporadic form. In addition, we evaluated the PDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A > G. The mRNA expression was fourfold lower in both patients with PDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-type PDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the potential impact of mutations in clinical interpretation as well as support to better understand the mechanism and pathogenesis of CCM3.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.